The brain peptide neurotensin (NT) and its active derivative NT [8-13] function as endogenous neuroleptics. Stable NT derivatives that cross the blood brain barrier therefore have significant potential for development as a new class of non-dopamineric antipsychotics expected not to display the adverse side effects associated with the dopaminergics. The best literature derivatives of NT [8-13] cross the BBB to a small extent (< 1 percent) and lose greater than 100-fold binding affinity for the NT-I receptor. One of these compounds was in clinical trials as an antischizophrenic before being dropped due to lack of l.V. activity. Using our patented technology for improving peptides as drug entities, we have synthesized and studied about 30 different NT [8-13] derivatives that drastically improve upon earlier compounds: NT receptor binding affinity is maintained or exceeded, the compounds exhibit up to 50 percent CNS bioavailability when l.V. Injected, their half-lives in serum have been increased from minutes to hours, and selectivities for each of the individual NT receptors has been observed. In the current proposal, we seek funding to: a) synthesize and study 12 "second generation" compounds predicted to show even better properties and b) evaluate our most active and representative compounds in two key predictive behavioral models of schizophrenia: a) antagonizing apomorphine reversal of prepulse inhibition of acoustic startle, b) blocking the locomotor activity stimulant effect of D-amphetamine. The best compounds emerging from these studies will be poised for development as a new class of antischizophrenic agents.